Piperazinyl-bis(alkylamino)pyrimidine derivatives and process for preparing same

ABSTRACT

An intermediate compound is disclosed that is useful in the preparation of a lipid-peroxidation inhibiting substance and that is selected from the group consisting of: 
     2,4-bis[1-adamantylamino]-6-(1-piperazinyl)pyrimidine; and 
     4,6-bis(1-adamantylamino)-2-(1-piperazinyl)pyrimidine; 
     or a pharmaceutically acceptable acid addition salt thereof.

This is a natural stage application under 37 C.F.R. 371 ofPCT/HU93/00034, filed Jun. 8, 1993.

FIELD OF THE INVENTION

The invention relates to novel piperazinyl-bis(alkylamino)pyrimidinederivatives of the formula ##STR1## wherein two of X, Y and Z mean anitrogen atom each and the third one is a methine group;

R¹ and R² are each, independently from each other, a primary amino groupbearing as substituent a branched-chain C₄₋₈ alkyl, -alkenyl or -alkynylgroup, or a C₄₋₁₀ cycloalkyl group comprising 1 to 3 ring(s) and beingoptionally substituted by C₁₋₃ alkyl group(s); or

R¹ and R² are each for a spiro-heterocyclic secondary amino groupcontaining at most 10 carbon atoms and optionally at least one oxygenatom as an additional heteroatom; or

one of R¹ and R² is an unsubstituted heterocyclic secondary amino groupcontaining 4 to 7 carbon atoms and the other one is an above-identifiedprimary amino group, an above-identified spiro-heterocyclic secondaryamino group, or a heterocyclic secondary amino group containing 4 to 7carbon atoms and substituted by C₁₋₄ alkyl group(s); and

n is 1 or 2,

as well as their acid addition salts.

Further, the invention relates to a process for the preparation of theabove compounds.

The compounds of the formula (I) according to the invention are new andpossess a significant biological activity in themselves; however, theiruse in the preparation of lipid peroxidation-inhibiting substances bearsa greater importance.

Hereinafter and in the claims primary amino groups are meant to containa hydrogen atom as one substituent whereas the other substituent is abranched-chain C₄₋₈ alkyl, -alkenyl or -alkynyl group, or a C₄₋₁₀cycloalkyl group, comprising 1 to 3 rings, and being optionallysubstituted by C₁₋₃ alkyl group(s). The branched-chain C₄₋₈ alkyl,-alkenyl and -alkynyl groups may be various iso-, sec- and teft-butyl,butenyl, pentyl, pentenyl, pentynyl, hexyl, hexenyl, hexynyl, pentyl,heptenyl, heptynyl, octyl, octenyl and octynyl groups. Preferredrepresentatives of these are the 1,1-dimethylethyl, 2,2-dimethylpropyland 4,4-dimethyl-1-penten-5-yl groups.

The C₄₋₁₀ cycloalkyl group comprising 1 to 3 rings and being optionallysubstituted by C₁₋₃ alkyl group(s) can be e.g. a cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or adamantyl group. These groupsmay be unsubstituted or bear one or more methyl, ethyl or propylgroup(s) as substituents.

As R¹ and R², the spiro-heterocyclic secondary amino group containing atmost 10 carbon atoms and optionally at least one additional oxygenheteroatom is exemplified by the 4,4-ethylenedioxy-1-piperidinyl group,without any limitation thereto.

When representing an unsubstituted heterocyclic secondary amino groupcontaining 4 to 7 carbon atoms, one of R¹ and R² may preferably be apyrrolidino, piperidino or azepino group. In this case, the other one ofR¹ and R² means either a primary amino group mentioned above, or anabove-defined secondary heterocyclic group having spiro structure, or anabove-defined heterocyclic secondary amino group containing 4 to 7carbon atoms and substituted by C₁₋₄ alkyl group(s). These C₁₋₄ alkylgroups may be the same or different, e.g. methyl, ethyl, n- orisopropyl, or n-, iso-, secor tert-butyl groups. A preferredrepresentative of these substituted heterocyclic secondary amino groupsis e.g. the 2,2,6,6-tetramethyl-1-piperidinyl group.

BACKGROUND OF THE INVENTION

Lipid peroxidation occurring as a consequence of injuries is a secondaryprocess. Some cells are immediately destroyed when the tissues aredamaged. During the next hours the injury is extended to the surroundingcells. This is induced by free oxygen radicals which attack the lipidlayer of the cellular membrane and may eventually lead to cell death bydamaging the membrane and releasing hydrogen peroxide. Compoundsinhibiting lipid peroxidation can prevent this secondary processoccurring as sequels of e.g. paralyses, cephalic or spinal traumas.Compounds possessing such an effect may be utilized e.g. for thetreatment of Alzheimer's disease, muscular dystrophy and the like.

The following publications discussing the preparation ofpiperazinylpyrimidine derivatives are known; the preparation ofantiinflammatory 2,4-diamino-6-piperazinylpyrimidine derivatives isdescribed in the GB patent specification No. 1,345,640. In the targetcompounds the amino groups, being the same or different, may bemonoalkylamino groups containing 1 to 6 carbon atoms, cycloalkylaminogroups containing at most 6 carbon atoms or a morpholino group whereasthe amino group in position 4 may be a piperazino group, too.

According to this patent specification the starting substance of thesynthesis is 2,4,6-trichloropyrimidine of the formula (IV) (seehereinafter) which is first reacted with morpholine, then the dichlorocompound obtained is brought into reaction with ethylamine, finally themonochloro compound formed is reacted with piperazine to give4-ethylamino-2-morpholino-6-(1-piperazinyl)pyrimidine as described inthe examples. Compounds containing a morpholino group as one of the twoamino groups and a cycloalkylamino or monoalkylamino group containing atmost 4 carbon atoms are indicated to be most effective. Among these inthe preferred compounds one of the two amino groups is ethylamino orcyclopropylamino group, the other one is a morpholino group. Detailedexamples with physical characteristics are given for the preparation of2-ethylamino-4-morpholino-6-(1-piperazinyl)pyrimidine and4-cyclopropylamino-2-morpholino-6-(1-piperazinyl)pyrimidine, too.

In the published German patent specification No. 2,630,1402,4-diaminopyrimidine derivatives are described, wherein the aminogroups are mono- or disubstituted; the substituents may be C₁₋₄ alkyl,C₂₋₄ alkenyl or cyclopropyl groups. A post-emergent herbicidal activityis attributed to these compounds.

The synthesis of [piperazinyl-bis(amino)pyrimidinyl]-steroids ofprimarily lipid peroxidation-inhibiting activity is described in thepublished PCT patent application No. WO 87/01706. There are givenexamples for the preparation of piperazinyl-bis(alkylamino)pyrimidinederivatives used as starting substances for the steroid derivativesmentioned above, too. Thus, 2,4,6-trichloropyrimidine is reactedprimarily with saturated or unsaturated amines containing 1 to 3 carbonatoms as well as pyrrolidine, morpholine, hexamethyleneimine orN-methylpiperazine. According to the biological data published in thisapplication, 4-(1-piperazinyl)-2,6-bis(pyrrolidino)pyrimidine proved tobe the most favourable one for the preparation of lipidperoxidation-inhibiting compounds.

It is known from the published PCT patent application No. WO P 91/11453that the strength of the lipid peroxidation-inhibiting effect issignificantly influenced by usingsome-piperazinyl-bis(alkylamino)pyrimidine derivatives as substituentsconnected e.g. to compounds having steroid skeleton or other substanceshaving a similar structure.

OBJECT OF THE INVENTION

The object of the present invention is aimed at the preparation ofanalogous piperazinylpyrimidine derivatives which, when used assubstituents, are capable of increasing the biological activity anddecreasing the toxicity of the molecules substituted by thesesubstituents, in comparison to known analogues.

SUMMARY OF THE INVENTION

Surprisingly, it has been found that the compounds of the formula (I)according to the invention are excellent for this purpose.

The piperazinylpyrimidine compounds according to the invention can beused as substituents for various compounds, e.g. pregnane derivatives.

The novel piperazinyl-bis(alkylamino)pyrimidine derivatives of theformula (I) can be prepared in such a way that

a) about 1 mole of a 2,4,6-trichloropyrimidine characterized by formula##STR2## wherein X, Y and Z are as defined above, is reacted with about1 mole of a primary or secondary amine of the formula R¹ -H, wherein R¹is as defined above,

the obtained isomeric mixture of a 2-amino-4,6-dichloropyrimidine of theformula ##STR3## and a 4-amino-2,6-dichloropyrimidine of the formula##STR4## wherein R¹ is as defined above, is separated to the individualisomers, and

about 1 mole of a thus obtained individual isomer is reacted with about1 mole of a primary or secondary amine of the formula R² -H, wherein R²is as defined above, then

after separating the isomeric mixture of diaminochloropyrimidines of theformula ##STR5## and formula ##STR6## wherein R¹ and R² are as definedabove, obtained from a 4-amino-2,6-dichloropyrimidine of the formula(IIIb), wherein R¹ is as defined above, to the individual isomers,

one of these individual isomers or a 2,6-diamino-4-chloropyrimidine ofthe formula ##STR7## wherein R¹ and R² are as defined above, obtainedfrom a 2-amino-4,6-dichloropyrimidine of the formula (IIIa), is reactedwith a piperazine derivative of the formula ##STR8## wherein n is 1 or2; or b) about 1 mole of a 2,4,6-trichloropyrimidine characterized bythe formula (IV), wherein X, Y and Z are as defined above, is reactedwith about 2 moles of a primary or secondary amine of the formula R¹ -H,wherein R¹ is as defined above, then after separating the obtainedisomeric mixture of diaminochloropyrimidines of the formulae (IIba)(IIbb), wherein R¹ and R² are the same as R¹ defined above, to theindividual isomers, one of these individual isomers is reacted with apiperazine derivative of the formula (V), wherein n is 1 or 2, in orderto obtain piperazinyl-bis(alkylamino)pyrimidine derivatives of theformula (I) bearing identical substituents as R¹ and R², wherein X, Y,Z, R¹, R² and n are as defined above,

and, if desired, a piperazinyl-bis(alkylamino)pyrimidine derivative ofthe formula (I) obtained, wherein X, Y, Z, R¹, R² and n are as definedabove, is converted into an acid addition salt by reacting it with anacid and/or a free base of the formula (I) is liberated from its acidaddition salt.

2,4,6-Trichloropyrimidine used as starting substance in the process ofthe invention is a well-known compound [Ber. 33, pages 3666 (1900) and37, page 3657 (1904); Chem. Abstr. Registration No. 3764-01-0]. Theprimary and secondary amines of the formulae R¹ -H and R² -H, as well asthe piperazine derivatives of the formula (V) are commercially availableproducts.

Depending on the reactivity of the amine, the reaction of a2,4,6-trichloropyrimidine of the formula (IV) with primary or secondaryamines of the formula R¹ -H may be carried out at a temperature between-20° C. and +40° C. with a reaction time of from 30 minutes up toseveral days. When using the sterically hindered2,2,6,6-tetramethylpiperidine (which may be used as a solvent, too) aboiling under reflux for about 50 hours is necessary at the boilingpoint of the reaction mixture for completing the reaction. Theworking-up of the reaction mixture as well as the recovery of theproduct are preferably carried out in such a manner that aftertermination of the reaction the solvent is distilled off, the residue isdissolved in a halogenated solvent, preferably chloroform, then thesolution is washed first with aqueous sodium hydroxide solution andsubsequently with water. After separation the organic phase is dried,the solvent is distilled off, then the two alkylamino-dichloropyrimidineisomers formed in the reaction are separated by chromatography on asilica gel column. The separated individual isomers are purified byrecrystallization.

After separation the isomeric alkylamino-dichloropyrimidine derivativesof the formula (IIIa) and (IIIb) obtained in the first step are againreacted with the same or different amine. The parameters of thisreaction are mainly dependent on the reactivity of the amine reactant.Thus, the reaction can be made complete at room temperature whenpyrrolidine is used as an amine; whereas a reaction lasting for about 15hours at 130° C. is needed in the case of tert-butylamine. The reactionof neopentylamine with the isomeric alkylamino-dichloropyrimidinederivatives can be carried out under milder conditions: this reactionbecomes complete by boiling in isopropanol for about 20 hours. The lessreactive 5-amino-4,4-dimethyl-1-pentene reacts with the isomericalkylamino-dichloropyrimidine derivatives only at higher temperatures.Due to its large space demand, 1-amino-adamantane should be reacted, byboiling in n-butanol for about 75 hours.

The recovery of the individual isomers from reaction mixtures containingthe diaminochloropyrimidine isomers of the formulae (IIba) and (IIbb),formed from 4-amino-2,6-dichloropyrimidine of the formula (IIIb) in thesecond step, can be achieved by using e.g. the method described abovefor the recovery of compounds of the formulae (IIIa) and (IIIb).

According to the invention the preparation of piperazinylpyrimidinederivatives of the formula (I) by reactingbis(alkylamino)-chloropyrimidine derivatives of formulae (IIa), (IIbb)or (IIba) with piperazine derivatives of formula (V) is suitably carriedout as described hereinafter.

The bis(alkylamino)-chloropyrimidine derivative of the formula (IIa) or(IIbb) or (IIba) is dissolved in a tertiary amine, preferablyN-ethylmorpholine, and boiled with an excess of the piperazinederivative of the formula (V) under nitrogen for about 25 hours. Afterthe reaction has become complete, N-ethylmorpholine used as solvent andthe major part of the excess of the piperazine derivative of the formula(V) are distilled off, water is added to the residue and distilled offagain. This repeated distillation is continued under atmosphericpressure until the head temperature reaches about 100° C. Afterdissolving the residue in chloroform the solution is washed first withaqueous sodium hydroxide solution, then with water. After separation theorganic phase is dried and the chloroform is distilled off. The residueis purified first by chromatography on a silica gel column and then byrecrystallization.

The advantage of using the piperazinyl-bis(alkylamino)pyrimidinederivatives of the formula (I) for the preparation of lipidperoxidation-inhibiting compounds is demonstrated on21-{4-[2,4-bis(adamantylamino)-6-pyrimidinyl]-1-piperazinyl}-16α-methylpregna-1,4,9(11)triene-3,20-dionemethanesulfonate.

The pharmacological study was carried out on unanesthetized mice byusing a known experimental cephalic trauma model [J. Neurosurg. 62, page882 (1980)] modified by us. In this study, the potentialcerebroprotective effects of intravenous (i.v.) doses of the compoundswere investigated.

A metal cleaver of defined weight was let fall onto a defined part ofthe scullcap surface of the experimental animals from a defined heightunder the force of gravity. Within 5 minutes following the closedcephalic injury induced by the cleaver, a suitable dose of the substanceunder test was injected to a tail vein of the animals and theneurological condition of the animals was evaluated in the 60th minutefollowing the cephalic trauma. This evaluation was performed using asimple grip test, to examine the effects of the trauma on the motorfunctions of both the upper and lower limbs. In addition, the frequencyof cases considered to be "mild" or "severe", based on predeterminedcriteria, as well as the ratio of animals suffering fromparaparesis-paraplegia were registered in the various treatment groups.The development of eventually occurring deficiency symptoms of thenervous system was made quantitative by comparison of the neurologicalcondition of animals treated with the active agent to the condition ofcontrols treated only with the vehicle.

When administered in the most favorable dose of 0.1 mg/kg,21-{4-[2,4-bis(adamantylamino)-6-pyrimidinyl]-1-piperazinyl}-16α-methylpregna-1,4,9(11)triene-3,20-dionemethanesulfonate increased by 33% the number of cases signed as "mild"(based on the neurological symptoms induced by the cephalic trauma) andsimilarly, it decreased by 33% the frequency of cases involvingparaparesis-paraplegia. The known tirilazad mesylate (see the publishedPCT patent application No. WO 87/01706), chemically16α-methyl-21-{4-[2,4-bis(pyrrolidino)-6-pyrimidinyl]-1-piperazinyl}Pregna-1,4,9(11)triene-3,20-dionemethanesulfonate, was used as control. When administered in the mosteffective dose of 0.3 mg/kg, tirilazad mesylate increased only by 23%the number of animals showing "mild" deficiency symptoms and decreasedonly by 20% the frequency of paraplegic animals.

Thus, it is obvious from the experimental results that the compoundsaccording to our invention increase the lipid peroxidation-inhibitingeffect of the basic substance to a higher grade in comparison to knowncompounds having a similar structure.

The invention is illustrated in detail by the aid of the followingnon-limiting Examples.

EXAMPLE 1

Preparation of 4,6-dichloro-2-pyrrolidinopyrimidine and2,4-dichloro-6-pyrrolidinopyrimidine

After dropping 23.7 ml (286.6 mmoles) of pyrrolidine to a mixturecontaining 25.0 g (136.3 mmoles) of 2,4,6-trichloropyrimidine in 200 mlof tetrahydrofuran at -20° C. within about 30 minutes, the cooling isstopped and after stirring for an additional 30 minutes the reactionmixture is evaporated. After distributing the residue between 500 ml ofchloroform and 50 ml of 10% sodium hydroxide solution, the organic phaseis separated, washed 4 times with 150 ml of water each, then dried andevaporated. The residue is subjected to chromatography on a silica gelcolumn. By using a 19:1 hexane/ethyl acetate mixture as eluent theeluate is evaporated and the evaporation residue is recrystallized fromhexane to give 7.51 g (25.27%) of 4,6-dichloro-2-pyrrolidinopyrimidine,m.p. 95°-98° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 6.51 (s, 1H, 5-H).

By further elution with a 4:1 mixture of the above solvent system2,4-dichloro-6-pyrrolidinopyrimidine as the more polar product isobtained in a yield of 20.22 g (68.03%) after recrystallization fromhexane, m.p.: 100.5°-103.5° C. ¹ H-NMR (60 MHz, CDCl₃) δ ppm: 6.18 (s,1H, 5-H).

EXAMPLE 2

Preparation of 4,6-dichloro-2-(1,1-dimethylethylamino)pyrimidine and2,6-dichloro-4-(1,1-dimethylethylamino)pyrimidine

25 g (136.6 mmoles) of 2,4,6-trichloropyrimidine are dropwise added to amixture of 31.52 ml of 1-amino-1,1-dimethylethane and 200 ml oftetrahydrofuran at a temperature between 10° C. and 15° C. while coolingand stirring. The reaction mixture is stirred at room temperature for anadditional 5 hours, then evaporated. After distributing the residuebetween 50 ml of chloroform and 50 ml of 10% sodium hydroxide solutionand separating, the organic phase is washed 4 times with 150 ml of watereach, then dried and evaporated. The residue is separated bychromatography on a silica gel column by using mixtures of hexane andethyl acetate as eluent. By using 9:1 hexane/ethyl acetate mixture4,6-dichloro-2-(1,1-dimethylethylamino)pyrimidine is eluated which isrecrystallized from hexane to obtain a yield of 11.35 g (37.84%), m.p.:70°-74° C.

¹ H-NMR (60 MHz, THF-d₈) δ ppm: 6.63 (s, 1H, 5-H).

By continuing the elution with a 4:1 mixture of the above solvent system2,6-dichloro-4-(1,1-dimethylethylamino)pyrimidine as a more polarproduct is obtained, which is recrystallized from ethyl acetate to give13.31 g (44.35%) of pure product, m.p.:192°-195° C.

¹ H-NMR (60 MHz, THF-d₈) δ ppm: 6.32 (s, 1H, 5-H).

EXAMPLE 3

Preparation of 4-chloro-2,6-bis(1,1-dimethylethylamino)pyrimidine

A solution containing 5.0 g of4,6-dichloro-2-(1,1-dimethylethylamino)pyrimidine in 25 ml of1-amino-1,1-dimethylethane is heated in a closed tube at 130° C. for 15hours. Thereafter, the reaction mixture is evaporated and theevaporation residue is distributed between 80 ml of chloroform and 15 mlof 10% sodium hydroxide solution. After separation the organic phase iswashed 4 times with 20 ml of water each, then dried and evaporated. Theevaporation residue is recrystallized from hexane to give the titlecompound in a yield of 5.45 g (93.4%), m.p.: 128°-130° C.

¹ H-NMR (60 MHz, THF-d₈) δ ppm: 5.67 (s, 1H, 5-H).

EXAMPLE 4

Preparation of2,4-bis(1,1-dimethylethylamino)-6-(1-piperazinyl)pyrimidine

A mixture containing 9.58 g (34.7 mmoles) of4-chloro-2,6-bis(1,1-dimethylethylamino)pyrimidine, 11.95 g (138.8mmoles) of piperazine and 150 ml of N-ethylmorpholine is boiled underreflux and nitrogen atmosphere for 25 hours, then the solvent and theexcess of piperazine are distilled off under atmospheric pressure.Subsequently, 100 ml of water are added to the residue and thedistillation is continued until the head temperature reaches 100° C.After cooling down, the residue is distributed between 200 ml ofchloroform and 30 ml of 10% sodium hydroxide solution. After separationthe organic phase is washed 4 times with 50 ml of water each, then driedand evaporated. The residue is purified by chromatography on a silicagel column by using a 9:1 mixture of chloroform/methanol as eluent.After evaporating the eluate the residue is recrystallized from hexaneto obtain the title compound in a yield of 64%, m.p.: 142°-145° C.

¹ H-NMR (60 MHz, CDCl ₃) δ ppm: 4.99 (s, 1H, 5-H).

EXAMPLE 5

Preparation of 6-chloro-2,4-bis (1,1-dimethylethylamino)pyrimidine and2-chloro-4,6-bis (1,1-dimethylethylamino) pyrimidine

A solution of 10 g of 2,6-dichloro-4-(1,1-dimethylethylamino)pyrimidinein 50 ml of 1-amino-1,1-dimethylethane is heated in a closed tube at130° C. for 15 hours. Thereafter, the reaction mixture is evaporated andthe residue is distributed between 150 ml of chloroform and 30 ml of 10%sodium hydroxide solution. After separation the organic phase is washed4 times with 10 ml of water each, then dried and evaporated. Theevaporation residue is subjected to chromatography on a silica gelcolumn by using a 9:1 mixture of hexane/ethyl acetate as eluent to give6-chloro-2,4-bis(1,1-dimethylethylamino) pyrimidine which isrecrystallized from hexane to result in a yield of 9.92 g (85.1%), m.p.:125°-127° C. By continuing the elution with a 4:1 mixture ofhexane/ethyl acetate 2-chloro-4,6-bis(1,1-dimethylethylamino)pyrimidineas a more polar product is obtained which is recrystallized from hexaneto result in a yield of 0.49 g (4.2%), m.p.: 132°-135° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 4.93 (s, 1H, 5-H).

EXAMPLE 6

Preparation of4,6-bis(1,1-dimethylethylamino)-2-(1-piperazinyl)pyrimidine

By reacting 2-chloro-4,6-bis(1,1-dimethylethylamino) -pyrimidine withpiperazine as described in Example 4, the title product is obtained in ayield of 76.5%, m.p.: 135°-138° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 4.83 (s, 1H, 5-H).

EXAMPLE 7

Preparation of1-[2,4-bis(1,1-dimethylethylamino)-6-pyrimidinyl]-hexahydro-1H-1,4-diazepine

By reacting 4-chloro-2,6-bis(1,1-dimethylethylamino)-pyrimidine withhexahydro-1H-1,4-diazepine as described in Example 4, the title productis obtained in a yield of 55.3%, m.p.: 127°-132° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 4.96 (s, 1H, 5-H).

EXAMPLE 8

Preparation of6-chloro-2-(1,1-dimethylethylamino)-4-(2,2-dimethylpropylamino)pyrimidine

After dissolving 5.0 g of4,6-dichloro-2-(1,1-dimethylethylamino)pyrimidine in 25 ml ofisopropanol and adding 5 ml of 1-amino-2,2-dimethylpropane the reactionmixture is boiled under reflux for 20 hours. Then, the reaction mixtureis evaporated and the residue is distributed between 80 ml of chloroformand 15 ml of 10% sodium hydroxide solution. After separation the organicphase is washed 4 times with 20 ml of water each, then dried andevaporated. After recrystallizing the evaporation residue from hexanethe title product is obtained in a yield of 4.49 g (73%), m.p.:109.5°-111° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.71 (s, 1H, 5-H).

EXAMPLE 9

Preparation of2-(1,1-dimethylethylamino)-4-(2,2-dimethylpropylamino)-6-(1-piperazinyl)pyrimidine

By reacting6-chloro-2-(1,1-dimethylethylamino)-4-(2,2-dimethylpropylamino)pyrimidinewith piperazine as described in Example 4, the title product is obtainedin a yield of 86.0%, m.p.: 120°-124° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 4.96 (s, 1H, 5-H).

EXAMPLE 10

Preparation of6-chloro-4-(1,1-dimethylethylamino)-2-(2,2-dimethylpropylamino)pyrimidine

After dissolving 5.0 g of2,4-dichloro-6-(1,1-dimethylethylamino)pyrimidine in 25 ml ofisopropanol and adding 5 ml of 1-amino-2,2-dimethylpropane, the reactionmixture is boiled under reflux for 20 hours. Subsequently, the reactionmixture is evaporated and the residue is distributed between 80 ml ofchloroform and 15 ml of 10% sodium hydroxide solution. After separationthe organic phase is washed 4 times with 20 ml of water each, then driedand evaporated. The evaporation residue is purified by chromatography ona silica gel column by using a 9:1 mixture of hexane/ethyl acetate aseluent. After recrystallizing the eluted product from hexane, the titleproduct is obtained in a yield of 4.05 g (65.9%), m.p.: 115°-119° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.66 (s, 1H, 5-H).

EXAMPLE 11

Preparation of4-(1,1-dimethylethylamino)-2-(2,2-dimethyl-propylamino)-6-(1-piperazinyl)pyrimidine

The reaction of4-chloro-6-(1,1-dimethylethylamino)-2-(2,2-dimethylpropylamino)pyrimidinewith piperazine as described in Example 4 gives the title product in ayield of 82.3%, m.p.: 146°-148° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.02 (s, 1H, 5-H).

EXAMPLE 12

Preparation of4-chloro-2-(1,1-dimethylethylamin)-6-pyrrolidinopyrimidine

After adding 10 g of 4,6-dichloro-2-(1,1-dimethylethylamino)pyrimidinein small portions to 40 ml of pyrrolidine at a temperature below 10° C.while cooling and stirring, the reaction mixture is stirred at roomtemperature for 1 hour and then evaporated. The residue is distributedbetween 150 ml of chloroform and 30 ml of 10% sodium hydroxide solution.After separation the organic phase is washed 4 times with 50 ml of watereach, then dried and evaporated. After recrystallizing the evaporationresidue from ethyl acetate the title product is obtained in a yield of10.76 g (93%), m.p.:153°-157° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.67 (s, 1H, 5-H).

EXAMPLE 13

Preparation of2-(1,1-dimethylethylamino)-4-(1-piperazinyl)-6-pyrrolidinopyrimidine

The reaction of4-chloro-2-(1,1-dimethylethylamino)-6-pyrrolidinopyrimidine withpiperazine as described in Example 4 gives the title product in a yieldof 78.1%, m.p.: 162°-165° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 4.87 (s, 1H, 5-H).

EXAMPLE 14

Preparation of4-chloro-6-(1,1-dimethylethylamino)-2-pyrrolidinopyrimidine

By reacting 2,4-dichloro-6-(1,1-dimethylethylamino)pyrimidine withpyrrolidine as described in Example 12, the title product is obtained ina yield of 73.8%, m.p.: 148°-150° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.62 (s, 1H, 5-H).

EXAMPLE 15

Preparation of4-(1,1-dimethylethylamino)-6-(1-piperazinyl)-2-pyrrolidinopyrimidine

4-Chloro-6-(1,1-dimethylethylamino)-2-pyrrolidinopyrimidine is reactedwith piperazine as described in Example 4 to give the title product in ayield of 67.5%, m.p.: 140°-145° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 4,90 (s, 1H, 5-H).

EXAMPLE 16

Preparation of 4,6-dichloro-2-(2,2-dimethylpropylamino)pyrimidine and2,6-dichloro-4-(2,2-dimethylpropylamino)pyrimidine

After dropwise adding 25 g (136.3 mmoles) of 2,4,6-trichloropyrimidineto the solution of 23.84 g (273.5 mmoles) of 1-amino-2,2-dimethylpropanein 200 ml of tetraydrofuran at a temperature between 10° C. and 15° C.under cooling and stirring, the reaction mixture is stirred at roomtemperature for an additional 30 minutes, then evaporated. Theevaporation residue is distributed between 300 ml of chloroform and 50ml of 10% sodium hydroxide solution. After separation the organic phaseis washed 4 times with 100 ml of water each, then dried and evaporated.The evaporation residue is subjected to chromatography on a silica gelcolumn by using mixtures of hexane and ethyl acetate as eluent. Byelution with a 19:1 mixture of hexane/ethyl acetate4,6-dichloro-2-(2,2-dimethylpropylamino) pyrimidine is obtained which isrecrystallized from a mixture of ether and hexane to give a yield of13.60 g (42.6%), m.p.: 63°-66° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 6.60 (s, 1H, 5-H).

By further elution with a 6:1 mixture of hexane/ethyl acetate2,6-dichloro-4-(2,2-dimethylpropylamino) pyrimidine is obtained, whichis recrystallized from a mixture of ether and hexane to result in ayield of 14.24 g (44.6%), m.p.:77°-79° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 6.33 (s, 1H, 5-H).

EXAMPLE 17

Preparation of 4-chloro-2,6-bis(2,2-dimethylpropylamino)pyrimidine

The reaction of 4,6-dichloro-2-(2,2-dimethylpropylamino)pyrimidine with1-amino-2,2-dimethylpropane as described in Example 10 affords the titleproduct in a yield of 49.4%, m.p.: 95°-98° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.71 (s, 1H, 5-H).

EXAMPLE 18

Preparation of2,4-bis(2,2-dimethylpropylamino)-6-(1-piperazinyl)pyrimidine

The reaction of 4-chloro-2,6-bis(2,2-dimethylpropylamino)pyrimidine withpiperazine as described in Example 4 gives the title product in a yieldof 51.5%, m.p.: 138°-140° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 4.98 (s, 1H, 5-H).

EXAMPLE 19

Preparation of 6-chloro-2,4-bis(2,2-dimethylpropylamino)pyrimidine and2-chlore-4,6-bis(2,2-dimethylpropylamino) pyrimidine

After dissolving 5.0 g of2,4-dichloro-6-(2,2-dimethyl-propylamino)pyrimidine in 25 ml ofisopropanol and adding 5 ml of 1-amino-2,2-dimethylpropane, the reactionmixture is boiled under reflux for 20 hours, then evaporated. Theevaporation residue is distributed between 80 ml of chloroform and 15 mlof 10% sodium hydroxide solution. After separation the organic phase iswashed 4 times with 20 ml of water each, then dried and evaporated. Theresidue is purified by chromatography on a silica gel column by usingmixtures of hexane and ethyl acetate as eluent. By eluting with a 99:1mixture 4-chloro-2,6-bis(2,2-dimethylpropylamino)pyrimidine is obtained,which is recrystallized from hexane to result in a yield of 5.00 g(82.3%), m.p.: 95°-97° C.

By further elution with a 19:1 mixture of the above solvent system2-chloro-4,6-bis(2,2-dimethylpropylamino)pyrimidine as a more polarproduct is obtained, which is recrystallized from hexane to give a yieldof 0.30 g (4.9%), m.p.: 178°-185° C.

EXAMPLE 20

Preparation of4,6-bis(2,2-dimethylpropylamino)-2-(1-piperazinyl)pyrimidine

The reaction of 2-chloro-4,6-bis(2,2-dimethylpropylamino)pyrimidine withpiperazine as described in Example 4 leads to the title product in ayield of 78.3%, m.p.: 132°-136° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 4.85 (s, 1H, 5-H).

EXAMPLE 21

Preparation of4-chloro-2-(2,2-dimethylpropylamino)-6-pyrrolidinopyrimidine

The reaction of 4,6-dichloro-2-(2,2-dimethylpropylamino)pyrimidine withpyrrolidine as described in Example 12 gives the title product in ayield of 96.7%, m.p.: 147°-150° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.67 (s, 1H, 5-H).

EXAMPLE 22

Preparation of2-(2,2-dimethylpropylamino)-4-(1-piperazinyl-6-pyrrolidinopyrimidine

By reacting 2-(2,2-dimethylpropylamino)-4-chloro-6-pyrrolidinopyrimidinewith piperazine as described in Example 4, the title compound isobtained in a yield of 76%, m.p.: 118°-120 °C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 4.83 (s, 1H, 5-H).

EXAMPLE 23

Preparation of4-chloro-6-(2,2-dimethylpropylamino)-2-pyrrolidinopyrimidine

The reaction of 2,4-dichloro-6-(2,2-dimethylpropylamino)pyrimidine withpyrrolidine as described in Example 12 affords the title compound in ayield of 75.0%, m.p.: 130°-135° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.72 (s, 1H, 5-H).

EXAMPLE 24

Preparation of4-(2,2-dimethylpropylamino)-6-(1-piperazinyl)-2-pyrrolidinopyrimidine

The reaction of4-chloro-6-(2,2-dimethylpropylamino)-2-pyrrolidinopyrimidine withpiperazine as described in Example 4 gives the title compound in a yieldof 76.0%, m.p.: 140°-145° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 4.93 (s, 1H, 5-H).

EXAMPLE 25

Preparation of4,6-dichloro-2-[(2,2-dimethyl-4-penten-1yl)-amino]pyrimidine and2,6-dichloro-4-[(2,2-dimethyl-4-penten-1-yl)amino]pyrimidine

4.59 (25 mmoles) of 2,4,6-trichloropyrimidine are added to a solution of6.23 g (55 mmoles) of 5-amino-4,4-dimethyl-1-pentene in 50 ml oftetrahydrofuran at room temperature, the reaction mixture is stirred atthe same temperature for 4 hours, then evaporated. The evaporationresidue is distributed between 60 ml of chloroform and 5 ml of 10%sodium hydroxide solution. After separation the organic phase is washed4 times with 10 ml of water each, then dried and evaporated. Theevaporation residue is subjected to chromatography on a silica gelcolumn by using mixtures of hexane and ethyl acetate as eluents. Elutionwith a 19:1 hexane/ethyl acetate mixture gives4,6-dichloro-2-[(2,2-dimethyl-4-penten-1-yl)amino]pyrimidine as an oilyproduct in a yield of 2.62 g (40.3%).

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 6.61 (s, 1H, 5-H).

By continuing the elution with a 9:1 mixture of hexane/ethyl acetate2,6-dichloro-4-[(2,2-dimethyl-4-penten-1-yl)amino]pyrimidine as a molarpolar product is obtained as an oil in a yield of 2.99 g (45.9%).

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 6.34 (s, 1H, 5-H).

EXAMPLE 26

Preparation of 4-chloro-2,6-[(2,2-dimethyl-4-penten-1-yl)amino]pyrimidine

After adding 2,29 (20.2 mmoles) of 5-amino-4,4-dimethyl-1-pentene to asolution containing 2.5 g (9.61 mmoles) of4,6-dichloro-2-[(2,2-dimethyl-4-penten-1-yl) amino]pyrimidine in 25 mlof n-butanol, the reaction mixture is boiled under reflux for 10 hours,then evaporated. The evaporation residue is distributed between 50 ml ofchloroform and 5 ml of 10% sodium hydroxide solution. After separationthe organic phase is washed 4 times with 10 ml of water each, then driedand evaporated. The evaporation residue is purified by chromatography ona silica gel column. By using a 19:1 mixture of hexane/ethyl acetate thetitle compound is obtained as an oily product in a yield of 2.25 g(69.5%).

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.70 (s, 1H, 5-H).

EXAMPLE 27

Preparation of2,4-bis[(2,2-dimethyl-4-penten-1-yl)amino]-6-(1-piperazinyl)pyrimidine

The reaction of 4-chloro-2,6-bis[(2,2-dimethyl-4-penten-5-yl)amino]pyrimidine with piperazine as described in Example 4 gives thetitle compound in a yield of 73.2%, m.p.: 72°-84° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 4.83 (s, 1H, 5-H).

EXAMPLE 28

Preparation of 2-(1-adamantylamino)-4,6-dichloropyrimidine and4-(1-adamantylamino)-2,6-dichloropyrimidine

After adding 40.6 g (225.6 mmoles) of 2,4,6-trichloropyrimidine to asolution of 70.3 g (465.6 mmoles) of 1-aminoadamantane in 650 ml oftetrahydrofuran, the reaction mixture is stirred for 24 hours, then theprecipitated crystalline 1-aminoadamantane hydrochloride precipitated isfiltered off and the filtrate is evaporated. By subjecting the residueto chromatography on a silica gel column by using a 49:1 mixture ofhexane/acetone 2-(1-adamantylamino)-4,6-dichloropyrimidine is obtainedwhich is recrystallized from hexane to result in a yield of 28.74 g(43.5%), m.p.: 151°-155° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 6.55 (s, 1H, 5-H).

By continuing the elution with a 24:1 mixture of hexane/acetone4-(1-adamantylamino)-2,6-dichloropyrimidine as the more polar product isobtained which is recrystallized similarly from hexane to result in ayield of 35.56 g (53.8%), m.p.: 193°-196° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 6.33 (s, 1H, 5-H).

EXAMPLE 29

Preparation of 2,4-bis(1-adamantylamino)-6-chloropyrimidine

The solution of 26.0 g (87.25 mmoles) of2-(1-adamantylaminio)-4,6-dichloropyrimidine and 39.5 g (261.6 mmoles)of 1-aminoadamantane in 200 ml of B-butanol is boiled under reflux for75 hours, then evaporated. The evaporation residue is suspended in 400ml of ether, filtered off, and the precipitate is dried, then purifiedby chromatography on a silica gel column, by using chloroform as eluent.The obtained product is recrystallized from ether to obtain the titlecompound in a yield of 23.94 g (66.44%), m.p.: 232°-236° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.64 (s, 1H, 5-H).

EXAMPLE 30

Preparation of 2,4-bis(1-adamantylamino)-6-(1-piperazinyl)pyrimidine

The reaction of 2,4-bis(1-adamantylamino)-6-chloropyrimidine withpiperazine as described in Example 4 gives the title compound in a yieldof 83.36%, m.p.: 168°-175° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 4.97 (s, 1H, 5-H).

EXAMPLE 31

Preparation of 2-(1-adamantylamino)-4-chloro-6-pyrrolidinopyrimidine

By reacting 2-(1-adamantylamino)-4,6-dichloropyrimidine with pyrrolidineas described in Example 12, the title compound is obtained in a yield of86%, m.p.: 178°-180° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.62 (s, 1H, 5-H).

EXAMPLE 32

Preparation of2-(1-adamantylamino)-4-(1-piperazinyl)-6-pyrrolidinopyrimidine

By reacting 2-(1-adamantylamino)-4-chloro-6-pyrrolidinopyrimidine withpiperazine as described in Example 4, the title compound is obtained ina yield of 69.7%, m.p.: 160°-164° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 4.87 (s, 1H, 5-H).

EXAMPLE 33

Preparation of 4-(1-adamantylamino)-6-chloro-2-pyrrolidinopyrimidine

4-(1-Adamantylamino)-2,6-dichloropyrimidine is reacted with pyrrolidineas described in Example 12 to obtain the title product in a yield of80.2%, m.p.: 186°-190° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.63 (s, 1H, 5-H).

EXAMPLE 34

Preparation of4-(1-adamantylamino)-6-(1piperazinyl)-2-pyrrolidinopyrimidine

4-(1-Adamantylamino)-6-chloro-2-pyrrolidinopyrimidine is reacted withpiperazine as described in Example 4 to give the title compound in ayield of 49.7%, m.p.: 152°-156° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 4.84 (s, 1H, 5-H).

EXAMPLE 35

Preparation of4,6-dichloro-2-(2,2,6,6-tetramethyl-1-piperidinyl)pyrimidine

The mixture of 25 g (136.3 mmoles) of 2,4,6-trichloropyrimidine and 46.3ml (272.6 mmoles) of 2,2,6,6-tetramethylpiperidine is boiled underreflux for 50 hours, then cooled down and suspended in 250 ml of hexane.The insoluble material is filtered off, the filtrate is evaporated andthe evaporation residue is distributed between 300 ml of chloroform and50 ml of 10% sodium hydroxide solution. After separation the organicphase is washed 4 times with 100 ml of water each, then dried andevaporated. The evaporation residue is purified by chromatography byusing hexane as eluent. After recrystallization of the obtained productfrom hexane, the title compound is obtained in a yield of 8.04 g(20.47%), m.p.: 89°-90° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 6.53 (s, 1H, 5-H).

EXAMPLE 36

Preparation of4-chloro-2-(2,2,6,6-tetramethyl-1-piperidinyl)-6-pyrrolidinopyrimidine

4,6-Dichloro-2-(2,2,6,6-tetramethyl-1-piperidinyl)pyrimidine is reactedwith pyrrolidine as described in Example 12 to give the title compoundin a yield of 75.08%, m.p.: 130°-135° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.76 (s, 1H, 5-H).

EXAMPLE 37

Preparation of2-(2,2,6,6-tetramethyl-1-piperidinyl)-4-(1-piperazinyl)-6-pyrrolidinopyrimidine

4-Chloro-2-(2,2,6,6-tetramethyl-1-piperidinyl)-6-pyrrolidinopyrimidineis reacted with piperazine as described in Example 42 to give the titlecompound in a yield of 80.2%, m.p.: 134°-137° C.

¹ H-NMa (60 MHz, CDCl₃) δ ppm: 5.01 (s, 1H, 5-H).

EXAMPLE 38

Preparation of2-(4,4-ethylenedioxy-1-piperidinyl)-4,6-dichloropyrimidine and4-(4,4-ethylenedioxy-1-piperidinyl)-2,6-dichloropyrimidine

After dropwise adding 43.32 g (286 mmoles) of1,4-dioxa-8-azaspiro[4,5]decane to a solution of 25 g (136.3 mmoles) of2,4,6-trichloropyrimidine in 200 ml of tetrahydrofuran at 0° C., thereaction mixture is stirred at room temperature for 1 hour, thenevaporated. The residue is distributed between 300 ml of chloroform and100 ml of 10% sodium hydroxide solution. After separating the organicphase is washed 4 times with 100 ml of water each, then dried andevaporated. The evaporation residue is subjected to chromatography on asilica gel column by using chloroform as eluent. The less polar2-(4,4-ethylenedioxy-1-piperidinyl)-4,6-dichloropyrimidine isrecrystallized from ethyl acetate to result in a yield of 13.98 g(35.36%), m.p.: 104°-105° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 6.50 (s, 1H, 5-H).

The more polar4-(4,4-ethylenedioxy-1-piperidinyl)-2,6-dichloropyrimidine is alsorecrystallized from ethyl acetate to result in a yield of 20.98 g(53.04%), m.p.: 133°-136° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 6.40 (s, 1H, 5-H).

EXAMPLE 39

Preparation of2,4-bis(4,4-ethylenedioxy-1-piperidinyl)-6-chloropyrimidine

After adding 2.6 ml (17.23 mmoles) of 1,4-dioxa-8-azaspiro[4,5]decane tothe solution of 2.0 g (6.89 mmoles) of2-(4,4-ethylenedioxy-1-piperidinyl)-4,6-dichloropyrimidine in 40 ml ofn-butanol, the reaction mixture is boiled under reflux for 4 hours, thenevaporated. The evaporation residue is distributed between 50 ml ofchloroform and 5 ml of 10% sodium hydroxide solution. After separationthe organic phase is washed 4 times with 10 ml of water each, then driedand evaporated. After recrystallizing the obtained product from hexanethe title compound is obtained in a yield of 2.51 g (91%), m.p.:130°-131° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.88 (s, 1H, 5-H).

Example 40

Preparation of2,4-bis(4,4-ethylenedioxy-1-piperidinyl)-6-(1-piperazinyl)pyrimidine

The reaction of2,4-bis(4,4-ethylenedioxy-1-piperidinyl)-6-chloropyrimidine withpiperazine as described in Example 4 gives the title compound in a yieldof 55.7%, m.p.: 130°-140° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.01 (s, 1H, 5-H).

Example 41

Preparation of2,4-bis(4,4-ethylenedioxy-1-piperidinyl)-6-chloropyrlmidine and4,6-bis(4,4-ethylenedioxy-1-piperidinyl)-2-chloropyrimidine

After adding 26 ml (172.3 mmoles) of 1,4-dioxa-8-azaspiro[4,5]decane toa solution of 20.0 g (68.9) mmoles) of2-(4,4-ethylenedioxy-1-piperidinyl)-4,6-dichloropyrimidine in 400 ml ofn-butanol, the reaction mixture is boiled under reflux for 4 hours, thenevaporated. The evaporation residue is distributed between 500 ml ofchloroform and 50 ml of 10% sodium hydroxide solution. After separationthe organic phase is washed 4 times with 100 ml of water each, thendried and evaporated. The evaporation residue is subjected tochromatography by using chloroform as eluent on a silica gel column. Theless polar 2,4-bis(4,4-ethylenedioxy-1-piperidinyl)-6-chloropyrimidineis recrystallized from ethyl acetate to give a yield of 16.58 g (73.6%),m.p.: 130°-131° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.87 (s, 1H, 5-H).

The more polar4,6-bis(4,4-ethylenedioxy-1-piperidinyl)-2--chloropyrimidine is alsorecrystallized from ethyl acetate to result in a yield of 2.66 g(11.8%), m.p.: 149°-150° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.48 (s, 1H, 5-H).

EXAMPLE 42

Preparation of4,6-bis(4,4-ethylenedioxy-1-piperidinyl)-2-(1-piperazinyl)pyrimidine

The reaction of4,6-bis(4,4-ethylenedioxy-1-piperidinyl)-2-chloropyrimidine withpiperazine as described in Example 4 gives the title compound in a yieldof 58.9%, m.p.: 122°-126° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 4.99 (s, 1H, 5-H).

EXAMPLE 43

Preparation of 2-cyclopentylamino-4,6-dichloroplrrimidine and2,6-dichloro-4-cyclopentylaminopyrimidine 2,4,6-Trichloropyrimidine isreacted with cyclopentylamine as described in Example 2 to obtain theless polar 2-cyclopentylamino-4,6-dichloropyrimidine in a yield of35.2%, m.p.: 48°-52° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 6.52 (s, 1H, 5-H).

The more polar 2,6-dichloro-4-cyclopentylaminopyrimidine is obtained asan oily product in a yield of 57.2%.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 6.30 (s, 1H, 5-H).

EXAMPLE 44

Preparation of 2-cyclopentylamino-4-chloro-6-pyrrolidinopyrimidine

2-Cyclopentylamino-4,6-dichloropyrimidine is reacted with pyrrolidine asdescribed in Example 12 to give the title compound as an oily product ina yield of 72.4%.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.72 (s, 1H, 5-H).

EXAMPLE 45

Preparation of2-cyclopentylamino-4-(1-piperazinyl)6-pyrrolidinopyrimidine2-Cyclopentylamino-4-chloro-6-pyrrolidinopyrimidine is reacted withpiperazine as described in Example 4 to afford the title compound in ayield of 63.8%, m.p.: 125°-128° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 4.84 (s, 1H, 5-H).

EXAMPLE 46

Preparation of 6-chloro-2,4-bis(2,2-dimethylpropylamino)pyrimidine and2-chloro-4,6-bis(2,2-dimethylpropylamino) pyrimidine

After dropwise adding 5.00 g (27.26 moles) of 2,4,6-trichloropyrimidineto the solution of 11.88 g (136.3 mmoles) of 1-amino-2,2-dimethylpropanein 50 ml of isopropanol while cooling and stirring, the reaction mixtureis boiled under reflux for 20 hours, then evaporated. The evaporationresidue is distributed between 80 ml of chloroform and 25 ml of 10%sodium hydroxide solution. After separation the organic phase is washed4 times with 20 ml of water each, then dried and evaporated. Theevaporation residue is subjected to chromatography by using a mixture ofhexane and ethyl acetate as eluent on a silica gel column. By carryingout the elution with a 99:1 mixture,6-chloro-2,4-bis(2,2-dimethylpropylamino)pyrimidine is obtained which isrecrystallized from hexane to give a yield of 5.74 g (73.9%), m.p.:95°-97° C.

By continuing the elution with a 19:1 mixture of hexane/ethyl acetate,the more polar 2-chloro-4,6-bis(2,2-dimethylpropylamino)pyrimidine isobtained which is recrystallized from hexane to give a yield of 0.16 g(2.8%), m.p.: 178°-185° C.

EXAMPLE 47

Preparation of21-(4-bromobenzenesulfonyloxy)-16α-methylpregna-1,4,9(11)-triene-3,20-dione

To a solution containing 10.0 g (29.4 moles) of21-hydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione in 100 mol oftetrahydrofuran, first 7,14 ml (51.4 mmoles) of triethylamine, then at0° C. 13.1 g (51.4 moles) of 4-bromobenzenesulfonyl chloride are added,the reaction mixture is stirred at room temperature for 4 hours, then itis dropwise added to 450 ml of water while stirring. The precipitate isfiltered off, dried and recrystallized from ether to obtain 11.0 g(67.07%) of the title compound, m.p.: 124°-129° C.

¹ H-NMR (300 MHz, CDCl₃) δ ppm: 0.65 (s, 3H, 18-CH₃), 0.93 (d, 1H,16α-CH₃), 1.40 (s, 3H, 19-CH₃), 4.54 es 4.66 (d, d, 2H, 21-CH₂), 5.50(m, 1H, 11-H), 6.07 (t, 1H, 4-H), 6.29 (dd, 1H, 2-H), 7.16 (d, 1H, 16H),7.72 (d, 2H, phenylene C3-H), C5-H), 7.83 (d, 2H, phenylene C2-H, C6-H).

EXAMPLE 48

Preparation of21-{4-[2,4-bis(1-adamantylamino)-6-pyrimidinyl]-1-piperazinyl}-16α-methylpregna-1,4,9(11)-triene-3,20-dione.

After adding 1.88 g (4.07 moles) of2,4-bis(1-adamantylamino)-6-(1-piperazinyl)pyrimidine and 0.56 g ofpotassium carbonate to a solution containing 2.00 g (3.57 mmoles) of21-(4-bromobenzenesulfonyloxy)-16α-methylpregna-1,4,9(11)-triene-3,20-dionein 100 ml of acetonitrile, the reaction mixture is stirred at 65° C. for5 hours, then evaporated. The residue is distributed between 40 ml ofchloroform and 10 ml of water. After separation the chloroform solutionis dried, evaporated and the residue is purified by chromatography on asilica gel column. A 98:2 mixture of chloroform/methanol is used forelution and the product obtained is recrystallized from ether to givethe title compound in a yield of 2.48 g (88.5%), m.p.: 210°-220° C.

¹ H-NMR (250 MHz, CDCl₃) δ ppm: 0.68 (s, 3H, 18-CH₃), 0.96 (d, 1H,16α-CH₃), 1.40 (s, 3H, 19-CH₃), 3.13 and 3.23 (d, d, 2H, 21-CH₂), 4.98(s, 1H, pyrimidine, C5-H), 5.51 (m, 1H, 11-H), 6.07 (m, 1H, 4-H), 6.28(d, d, 1H, 2-H), 7.16 (d, 1H, 1-H).

EXAMPLE 49

Preparation of 2,4-bis(1-adamantylamino)-6-chloropyrimidine and4,6-bis(1-adamantylamino)-2-chloropyrimidine

26.0 g (87.25 mmoles) of 4-(1-adamantylamino)-2,6-dichloropyrimidine and39.5 g (261.6 mmoles) of 1-aminoadamantane are dissolved in 200 ml ofn-butanol, then the reaction mixture is boiled for 75 hours andevaporated. The residue is suspended in 400 ml of ether and filtered.The recovered material is chromatographed after drying on a silica gelcolumn by using chloroform as eluent. The obtained substance is amixture of the title isomers. These are separated on a silica gel columnby using a mixture of hexane and ethyl acetate. By using a 49:1 mixtureof these solvents as eluent 2,4-bis(1-adamantylamino)-6-chloropyrimidineis obtained which is recrystallized to obtain a yield of 21.67 g(60.14%).

By continuing the elution with a 6:1 mixture of said solvents the morepolar 4,6-bis(1-adamantylamino)-2-chloropyrimidine is obtained which isrecrystallized from hexane to obtain a yield of 1.88 g (5.22%), meltingpoint: 260°-266° C.

¹ H-NMR (250 MHz, CDCl₃) δ ppm: 5.49 (s, 1H, 5-H).

EXAMPLE 50

Preparation of 4,6-bis(1-adamantylamine)-2-(1-piperazinyl)-pyrimidine

4,6-Bis(1-adamantylamino)-2-chloropyrimidine is reacted with piperazineas described in Example 4 to obtain the title compound in a yield of94.4%, m.p.: 210°-220° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 4.97 (s, 1H, 5-H).

EXAMPLE 51

Preparation of 2,4-bis(cyclopentylamino)-6-chloropyrimidine

5.0 g of 2-(cyclopentylamino)-4,6-dichloropyrimidine are dissolved in 25ml of isopropanol, then 7.5 ml of cyclopentylamine are added and themixture is boiled for 6 hours. Then the reaction mixture is evaporated,the residue is separated between 80 ml of chloroform and 15 ml of 10%sodium hydroxide solution. After separation the organic phase is washed4 times with 20 ml of water each, dried and evaporated. The titlecompound is obtained by recrystallizing from hexane in a yield of 5.24 g(86.7%), m.p.: 94°-98° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 5.67 (s, 1H, 5-H).

EXAMPLE 52

Preparation of 2,4-bis(cyclopentylamino)-6-(1-piperazinyl)pyrimidine2,4-Bis(cyclopentylamino)-6-chloropyrimidine is reacted with piperazineas described in Example 4 to give the title compound in a yield of81.9%, m.p.: 142°-148° C.

¹ H-NMR (60 MHz, CDCl₃) δ ppm: 4.94 (s, 1H, 5-H).

We claim:
 1. A compound selected from the group consisting of:2,4-bis[1-adamantylamino]-6-(1-piperazinyl)pyrimidine; and4,6-bis(1-adamantylamino)-2 -(1-piperazinyl)pyrimidine;or apharmaceutically acceptable acid addition salt thereof. 2.2,4-bis[1-adamantylamino]-6-(1-piperazinyl)pyrimidine or apharmaceutically acceptable acid addition salt thereof as defined inclaim 1.